Role of water in the multifaceted catalytic antibody 4B2 for allylic isomerization and kemp elimination reactions

Research output: Contribution to journalArticle

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Abstract

Specificity toward a single reaction is a well-known characteristic of catalytic antibodies. However, contrary to convention, catalytic antibody 4B2 possesses the ability to efficiently catalyze two unrelated reactions: a Kemp elimination and an allylic isomerization of a β,γ-unsaturated ketone. To elucidate how this multifaceted antibody operates, mixed quantum and molecular mechanics calculations coupled to Monte Carlo simulations were carried out. The antibody was determined to derive its adaptability for the mechanistically different reactions through the rearrangement of water molecules in the active site into advantageous geometric orientations for enhanced electrostatic stabilization. In the case of the Kemp elimination, a general base, Glu L34, carried out the proton abstraction from the isoxazole ring of 5-nitro-benzisoxazole while water molecules delivered specific stabilization at the transition state. The role of water was found to be more pronounced in the allylic isomerization because the solvent actively participated in the stepwise mechanism. A rate-limiting abstraction of the a-proton from the β,γ-unsaturated ketone via Glu L34 led to the formation of a neutral dienol intermediate, which was rapidly reprotonated at the y-position via a solvent hydronium ion. Preferential channeling of H3O+ in the active site ensured a stereoselective proton exchange from the a- to the y-position, in good agreement with deuterium exchange NMR and HPLC experiments. Ideas for improved water-mediated catalytic antibody designs are presented. In a technical advancement, improvements to a recent polynomial fitting and integration technique utilizing free energy perturbation theory delivered greater accuracy and speed gains.

Original languageEnglish (US)
Pages (from-to)15372-15381
Number of pages10
JournalJournal of Physical Chemistry B
Volume113
Issue number46
DOIs
StatePublished - Nov 19 2009
Externally publishedYes

Fingerprint

Catalytic Antibodies
Isomerization
antibodies
isomerization
elimination
Protons
Water
Ketones
Antibodies
water
Stabilization
ketones
protons
Isoxazoles
stabilization
Molecular mechanics
Molecules
Deuterium
Quantum theory
hydronium ions

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films

Cite this

Role of water in the multifaceted catalytic antibody 4B2 for allylic isomerization and kemp elimination reactions. / Acevedo, Orlando.

In: Journal of Physical Chemistry B, Vol. 113, No. 46, 19.11.2009, p. 15372-15381.

Research output: Contribution to journalArticle

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